Diabetic nephropathy is a major long-term complication of diabetic mellitus, which is the most common cause of end-stage renal disease and associated with the highest mortality in the US. Diabetic nephropathy is characterized by glomerular and tubuloepithelial hypertrophy, albuminuria, and glomerulosclerosis and tubulointerstitial fibrosis. The intrarenal renin-angiotensin system (RAS) and TGF-[unreadable] have been shown to play a critical role in the pathogenesis of diabetic nephropathy. As a major endocrine hormone produced by the kidney and targeting the kidney, 1,25-dihydroxyvitmain D3, possesses anti-proliferative activity and functions as an endocrine suppressor of the RAS. vitamin D-deficiency has been linked to renal failure and associated complications; however, the role of vitamin D in diabetic nephropathy is unknown. Based on recent evidence and our preliminary studies we hypothesize that 1,25-dihydroxyvitamin D3 plays a protective role in the pathogenesis and renal injury of diabetic nephropathy. To test this hypothesis, we propose three specific aims. The first aim is to define the molecular mechanism whereby 1,25-dihydroxyvitmain D3 inhibits high glucose-induced mesangial cell proliferation and extracelluar matrix production, focusing on the intrarenal RAS and TGF- [unreadable] signaling; the second aim is to study the role of the vitamin D receptor (VDR) in the protection against diabetic nephropathy, using streptozotocin (STZ)-induced diabetic VDR knockout mice and diabetic db/db mice that lack the VDR; the third aim is to explore the therapeutic potential of low calcemic vitamin D analogs in the protection against hyperglycamia-induced renal injury in STZ-induced diabetic C57BL6 mice and in spontaneous diabetic db/db mice. Our preliminary data have demonstrated that treatment of STZ- induced normal mice with such an analog indeed offers renal protection with little calcemic side effect. These exploratory studies will enhance our understanding of a novel aspect of vitamin D physiology and provide a basis for exploring the therapeutic potential of vitamin D analogs in prevention and treatment of diabetic nephropathy. [unreadable] [unreadable]